Scorpion venoms are complex mixtures that contain a large number of small basic proteins (M.W. about 7,000). These neurotoxins interact with the sodium channels of excitable membranes to enhance the inward sodium current and to delay sodium current inactivation. Their toxic effects are a consequence of the depolarization of receptive cells. The physiological and toxic effects of the scorpion toxins are alleviated by calcium. The present investigation is part of a multidisciplinary program to elucidate the structure-function relationships of various toxins derived from the venom of the scorpion Centruroides sculpturatus Ewing (CsE) (range, southwestern U.S.A.). Using NMR spectroscopy, the solution structures of various homologous toxins from CsE will be determined and compared with the crystallographic conformation available for the variant-3 toxin. In addition, our NMR investigation will test a number of hypotheses related to the proposed structure-function relationships among these interesting neurotoxins. A diverse number of mutually complementary NMR techniques, e.g., nuclear Overhauser effects, ring current calculations, amide hydrogen exchange, CIDNP, 2D-NOE etc., will be employed in our investigation. These studies will ultimately provide the background information necessary to use the neurotoxins as structural probes of sodium channels.